title: KEAP1-dependent synthetic lethality induced by AKT and TXNRD1 inhibitors in lung cancer.
abstract: Intrinsic resistance to agents targeting phosphoinositide 3-kinase (PI3K)/AKT pathway is one of the major challenges in cancer treatment with such agents. The objective of this study is to identify the genes or pathways that can be targeted to overcome the resistance of non-small cell lung carcinoma (NSCLC) to the AKT inhibitor MK2206, which is currently being evaluated in phase I and II clinical trials. Using a genome-wide siRNA library screening and biologic characterization, we identified that inhibition of thioredoxin reductase-1 (TXNRD1), one of the key antioxidant enzymes, with siRNAs or its inhibitor, auranofin, sensitized NSCLC cells to MK2206 treatment in vitro and in vivo. We found that simultaneous inhibition of TXNRD1 and AKT pathways induced robust reactive oxygen species production, which was involved in c-jun-NH2-kinase (JNK; MAPK8) activation and cell apoptosis. Furthermore, we found that the synthetic lethality interaction between the TXNRD1 and AKT pathways occurred through the KEAP1/NRF2 cellular antioxidant pathway. Finally, we found that synthetic lethality induced by TXNRD1 and AKT inhibitors relied on wild-type KEAP1 function. Our study indicates that targeting the interaction between AKT and TXNRD1 antioxidant pathways with MK2206 and auranofin, a U.S. Food and Drug Administration-approved drug, is a rational strategy to treat lung cancer and that KEAP1 mutation status may offer a predicative biomarker for such combination approaches.
authors.affiliation: Departments of Thoracic and Cardiovascular Surgery, Bioinformatics and Computational Biology, and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Dai
authors.forename: Suk-Young
authors.initials: SY
authors.lastname: Yoo
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Bartholomeusz
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Graham
authors.forename: Mourad
authors.initials: M
authors.lastname: Majidi
authors.forename: Shaoyu
authors.initials: S
authors.lastname: Yan
authors.forename: Jieru
authors.initials: J
authors.lastname: Meng
authors.forename: Lin
authors.initials: L
authors.lastname: Ji
authors.forename: Kevin
authors.initials: K
authors.lastname: Coombes
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Bingliang
authors.initials: B
authors.lastname: Fang
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D017209:Apoptosis; D001310:Auranofin / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D005804:Genes, Lethal; D005978:Glutathione / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D008856:Microscopy, Fluorescence; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009367:Neoplasm Staging; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D018501:Antirheumatic Agents; D006575:Heterocyclic Compounds, 3-Ring; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; C548887:MK 2206; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D001310:Auranofin; D008156:Luciferases; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D051057:Proto-Oncogene Proteins c-akt; D005978:Glutathione